c-Jun N-Terminal Kinase in Inflammation and Rheumatic Diseases.

The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family and are activated by environmental stress. JNK is also activated by proinflammatory cytokines, such as TNF and IL-1, and Toll-like receptor ligands. This pathway, therefore, can act as a critical convergence point in immune system signaling for both adaptive and innate responses. Like other MAPKs, the JNKs are activated via the sequential activation of protein kinases that includes two dual-specificity MAP kinase kinases (MKK4 and MKK7) and multiple MAP kinase kinase kinases. MAPKs, including JNKs, can be deactivated by a specialized group of phosphatases, called MAP kinase phosphatases. JNK phosphorylates and regulates the activity of transcription factors other than c-Jun, including ATF2, Elk-1, p53 and c-Myc and non-transcription factors, such as members of the Bcl-2 family. The pathway plays a critical role in cell proliferation, apoptosis, angiogenesis and migration. In this review, an overview of the functions that are related to rheumatic diseases is presented. In addition, some diseases in which JNK participates will be highlighted

Circulating Pro- and Anti-Inflammatory Metabolites and Its Potential Role in Rheumatoid Arthritis Pathogenesis.

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved the treatment of RA, patients often inquire about dietary interventions to improve RA symptoms, as they perceive pain and/or swelling after the consumption or avoidance of certain foods. There is evidence that some foods have pro- or anti-inflammatory effects mediated by diet-related metabolites. In addition, recent literature has shown a link between diet-related metabolites and microbiome changes, since the gut microbiome is involved in the metabolism of some dietary ingredients. But diet and the gut microbiome are not the only factors linked to circulating pro- and anti-inflammatory metabolites. Other factors including smoking, associated comorbidities, and therapeutic drugs might also modify the circulating metabolomic profile and play a role in RA pathogenesis. This article summarizes what is known about circulating pro- and anti-inflammatory metabolites in RA. It also emphasizes factors that might be involved in their circulating concentrations and diet-related metabolites with a beneficial effect in RA

Fibroblast-Like Synoviocytes Glucose Metabolism as a Therapeutic Target in Rheumatoid Arthritis.

Metabolomic studies show that rheumatoid arthritis (RA) is associated with metabolic disruption that may be therapeutically targetable. Among them, glucose metabolism and glycolytic intermediaries seem to have an important role in fibroblast-like synoviocytes (FLS) phenotype and might contribute to early stage disease pathogenesis. RA FLS are transformed from quiescent to aggressive and metabolically active cells and several works have shown that glucose metabolism is increased in activated FLS. Glycolytic inhibitors reduce not only FLS aggressive phenotype in vitro but also decrease bone and cartilage damage in several murine models of arthritis. Essential glycolytic enzymes, including hexokinase 2 (HK2) and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB) enzymes, have important roles in FLS behavior. Of interest, HK2 is an inducible enzyme present only in the inflamed rheumatic tissues compared to osteoarthritis synovium. It is a contributor to glucose metabolism that could be selectively targeted without compromising systemic homeostasis as a novel approach for combination therapy independent of systemic immunosuppression. More information about metabolic targets that do not compromise global glucose metabolism in normal cells is needed

Metabolomic profiling predicts outcome of rituximab therapy in rheumatoid arthritis.

ObjectiveTo determine whether characterisation of patients' metabolic profiles, utilising nuclear magnetic resonance (NMR) and mass spectrometry (MS), could predict response to rituximab therapy. 23 patients with active, seropositive rheumatoid arthritis (RA) on concomitant methotrexate were treated with rituximab. Patients were grouped into responders and non-responders according to the American College of Rheumatology improvement criteria, at a 20% level at 6 months. A Bruker Avance 700 MHz spectrometer and a Thermo Scientific Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer were used to acquire (1)H-NMR and ultra high pressure liquid chromatography (UPLC)-MS/MS spectra, respectively, of serum samples before and after rituximab therapy. Data processing and statistical analysis were performed in MATLAB. 14 patients were characterised as responders, and 9 patients were considered non-responders. 7 polar metabolites (phenylalanine, 2-hydroxyvalerate, succinate, choline, glycine, acetoacetate and tyrosine) and 15 lipid species were different between responders and non-responders at baseline. Phosphatidylethanolamines, phosphatidyserines and phosphatidylglycerols were downregulated in responders. An opposite trend was observed in phosphatidylinositols. At 6 months, 5 polar metabolites (succinate, taurine, lactate, pyruvate and aspartate) and 37 lipids were different between groups. The relationship between serum metabolic profiles and clinical response to rituximab suggests that (1)H-NMR and UPLC-MS/MS may be promising tools for predicting response to rituximab

Design of an anti-inflammatory diet (ITIS diet) for patients with rheumatoid arthritis.

Background:Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical advances have improved treatment of RA, patients with RA often inquire about dietary interventions to improve RA symptoms, as they perceive rapid changes in their symptoms after consumption of certain foods. There is evidence that some ingredients have pro- or anti-inflammatory effects. In addition, recent literature has shown a link between diet and microbiome changes. Both diet and the gut microbiome are linked to circulating metabolites that may modulate inflammation. However, evidence of the effects of an anti-inflammatory and probiotic-rich diet in patients with RA is scarce. There is also a need for biological data to support its anti-inflammatory effects. Methods:The main goal of this study is to delineate the design process for a diet tailored to our RA population. To achieve this goal, we collected information on diet, supplements, cooking methods, and intake of different ingredients for each patient. Different groups were interviewed, and their feedback was assessed to design a diet that incorporates suggested anti-inflammatory ingredients in a manner that was easy for patients to adopt based on their lifestyles and backgrounds. Results:We designed a diet that includes a high intake of potential anti-inflammatory ingredients. Feedback from highly motivated patients was critical in constructing an anti-inflammatory diet (ITIS diet) with elevated adherence. Conclusion:In order to tailor our diet, we surveyed our patients on several different parameters. We obtained important feedback on how feasible our ITIS diet is for RA patients. Using this feedback, we made minor improvements and finalized the design of the ITIS diet. This diet is being used in an on-going pilot study to determine their anti-inflammatory effect in pain and joint swelling in RA patients. Trial registration:Not applicable

Granulomatous fasciitis followed by morphea profunda: Is granulomatous fasciitis part of a spectrum of deep morphea? A case report and review of the literature.

Although eosinophilic fasciitis is known to be part of the deep morphea spectrum, this first report of the coexistence of granulomatous fasciitis and morphea profunda suggests that granulomatous fasciitis may also be a part of the spectrum of deep morphea